CN103724384A - Preparation method of cortisone acetate - Google Patents
Preparation method of cortisone acetate Download PDFInfo
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- CN103724384A CN103724384A CN201210380476.3A CN201210380476A CN103724384A CN 103724384 A CN103724384 A CN 103724384A CN 201210380476 A CN201210380476 A CN 201210380476A CN 103724384 A CN103724384 A CN 103724384A
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Abstract
The invention discloses a preparation method of cortisone acetate, and belongs to the field of pharmaceutical chemistry. According to the method, 11 alpha-hydroxy- 16 alpha, 17 alpha-epoxy progesterone is used as a raw material to prepare the cortisone acetate through bromine reaction, debromination reaction, bromination reaction, replacement reaction and oxidation reaction. The method can effectively avoid the occurrence of side reactions, and improves the quality of the product; at the same time, iodine is replaced by low-cost bromine for halogenating reaction, the production cost is greatly reduced, the method is high in efficiency and low in energy consumption, and the product quality and yield are good.
Description
Technical field
A kind of preparation method who the present invention relates to the synthetic field of medicine steroidal compounds, particularly a kind of preparation method of cortisone acetate, belongs to chemical pharmacy field.
Background technology
Cortisone acetate (Cortisone Acetate) claim again Cortisone (Adreson), chemical name is 4-pregnene-17 α, 21-glycol-3,11,20-triketone 21-acetic ester, being one of kind of market demand maximum in steroid hormone class bulk drug, is also the important intermediate of other high added value steroid drugss of preparation.China, the U.S. and European Pharmacopoeia etc. all record at present.Its structural formula is:
Cortisone acetate is middle effect adrenal cortex hormones drug, act on carbohydrate metabolism, electrolyte metabolism is had to certain influence, can alleviate body tissue and damaging be stimulated to the pathologic reaction producing, for the anaphylactic diseases such as serious bronchial asthma, serious dermatitis, the diseases such as reactivity rheumatosis, rheumatoid arthritis, lupus erythematosus.The synthetic method of cortisone acetate generally includes two kinds of chemical synthesis and semi-synthesis methods, chemical synthesis because of operational path long, reaction type complexity, total recovery is lower, does not have industrial production to be worth.In scale production at present, nearly all adopt the semi-synthesis method that does raw material containing the biomass of steroidal parent nucleus.By 16 α, 17 α-epoxy Progesterone is α-OH(11 Alpha-hydroxy-16 α in the oxidation of C11 position bread mould first, 17 α-epoxy Progesterone) after, through be oxidized the upper α-OH of C11 with chromic trioxide, it is ketone group, go up again bromine debrominate, upper iodization obtains cortisone acetate, 21 functional group's transformation process in this reaction scheme: the halogenating reaction that is first carbonyl α-H, then carry out replacement(metathesis)reaction and obtain target product cortisone acetate, the expensive iodine of domestic common employing does auxiliary material at present, greatly increased production cost, while is due to the existence of 11 carbonyls, cause in upper iodine process selectivity poor, side reaction is many, the equal Shortcomings of quality and yield, therefore the novel process of a kind of high-efficiency low energy consumption of feature development by response feature and functional group is very significant.
Summary of the invention
The present invention is for providing a kind of preparation method of new a kind of cortisone acetate.
The preparation method of a kind of cortisone acetate provided by the present invention, with 11 Alpha-hydroxy-16 α, 17 α-epoxy Progesterone is raw material, comprises the following steps:
(a) upper bromine reaction:
By 11 Alpha-hydroxy-16 α, 17 α-epoxy Progesterone adds in bromine hydracid, in 5 ~ 10 ℃ of stirring reactions, more than 5 hours, reacts complete, adds water elutriation, filters, and washes with water to neutrality, dry, obtains 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone;
(b) debromination:
By 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone add and in ethanol, are warming up to 40-45 ℃ of stirring and dissolving, then add successively glacial acetic acid, active Raney's nickel logical hydrogen, insulation reaction 3 hours, filters, and concentrating under reduced pressure reclaims solvent, filtered water is washed till neutrality, dry, obtain 11 α, 17 alpha-dihydroxy-Progesterone;
(c) bromination reaction:
By 11 α, 17 alpha-dihydroxy-Progesterone add in chloroform, then add hydrochloric acid-alcohol mixed solution stirring and dissolving, in 20 ~ 25 ℃, drip bromine liquid, finish, continue to stir 1 one hours, elutriation, filters, be washed to neutrality, be dried to obtain 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone;
(d) replacement(metathesis)reaction:
By 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone joined in Potassium ethanoate-dipolar aprotic solvent, in 35-40 ℃ of reaction 30 minutes, reclaim under reduced pressure dipolar aprotic solvent, filters, and is washed to neutrality, dry, obtain 11 α, 17 alpha-dihydroxy-s-21-acetic ester Progesterone;
(e) oxidizing reaction:
By 11 α, 17 alpha-dihydroxy-s-21-acetic ester Progesterone joins in glacial acetic acid, stirs, then adds the Manganous chloride tetrahydrate aqueous solution, 5-10 ℃ starts to drip chromium anhydride solution, adds rear insulation reaction more than 4 hours, elutriation, filter, be washed to neutrality, obtain cortisone acetate.
11 Alpha-hydroxy-16 α in described step (a), 17 α-epoxy Progesterone: bromine hydracid=1g:3 ~ 5ml, 11 α in described step (b), 17 alpha-dihydroxy--16 β-bromine Progesterone: ethanol: glacial acetic acid: Raney's nickel=1g:20 ~ 25ml:0.8 ~ 1.0ml:0.5 ~ 0.7g, 11 α in described step (c), 17 alpha-dihydroxy-s-Progesterone: chloroform: hydrochloric acid-alcohol mixeding liquid: the amount ratio of bromine liquid is 1g:7ml:0.2ml:3.6ml, described bromine liquid is the mixture of bromine and chloroform, bromine: the ratio of chloroform is 0.6ml:3ml, hydrochloric acid in described hydrochloric acid-alcohol mixeding liquid: ethanol is 4ml:1ml, 11 α in described step (d), 17 alpha-dihydroxy-s-21-bromine Progesterone: the amount ratio of Potassium ethanoate-dipolar aprotic solvent is 1g:15.97ml, in described step (d), dipolar aprotic solvent is dimethyl formamide or dimethyl sulfoxide (DMSO), in described step (d), the preparation method of Potassium ethanoate-dipolar aprotic solvent is: the salt of wormwood of proportional quantity is joined in dipolar aprotic solvent, be heated to 50 ℃, drip glacial acetic acid, finish and continue reaction 30 minutes, wherein salt of wormwood: dipolar aprotic solvent: the amount ratio of glacial acetic acid is: 1g:10.9ml:0.4ml, 11 α in described step (e), 17 alpha-dihydroxy-s-21-acetic ester Progesterone: in glacial acetic acid: the Manganous chloride tetrahydrate aqueous solution: the amount ratio of chromium anhydride solution is 1g:0.8ml:0.8ml:0.3ml, described manganese chloride solution concentration is 1g/ml, described chromium anhydride solution concentration is 1g/ml.
The preparation method of a kind of cortisone acetate provided by the present invention is a brand-new synthesis route, adopts a brand-new intermediate to carry out the halogenating reaction of carbonyl α-H, has avoided the generation of side reaction, has improved the quality of product; With bromine cheaply, replace expensive iodine to carry out halogenating reaction simultaneously, greatly saved production cost, high-efficiency low energy consumption of the present invention, quality product and yield are all better, and HPLC content reaches more than 98%, and yield reaches 103% left and right.
Embodiment
In order to explain more fully enforcement of the present invention, provide embodiment of the present invention.These embodiments are only the elaborations to this technique, do not limit the scope of the invention.
Raw materials used 11 Alpha-hydroxy-16 α in the present invention, 17 α-epoxy Progesterone can directly obtain from market, in the present invention, solid materials measures with g(grams) metering, with material (g), represent, liquid material measures with ml(milliliter) metering, with material (ml), represent, the g:ml form that the ratio of material adopts represents the ratio of grams and milliliter number, and TLC refers to tlc.
A preparation method for cortisone acetate, with 11 Alpha-hydroxy-16 α, 17 α-epoxy Progesterone is raw material, comprises the following steps:
(a) upper bromine reaction:
By 11 Alpha-hydroxy-16 α, 17 α-epoxy Progesterone adds in bromine hydracid, in 5 ~ 10 ℃ of stirring reactions, more than 5 hours, reacts complete, adds water elutriation, filters, and washes with water to neutrality, dry, obtains 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone;
(b) debromination:
By 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone add and in ethanol, are warming up to 40-45 ℃ of stirring and dissolving, then add successively glacial acetic acid, active Raney's nickel logical hydrogen, insulation reaction 3 hours, filters, and concentrating under reduced pressure reclaims solvent, filtered water is washed till neutrality, dry, obtain 11 α, 17 alpha-dihydroxy-Progesterone;
(c) bromination reaction:
By 11 α, 17 alpha-dihydroxy-Progesterone add in chloroform, then add hydrochloric acid-alcohol mixed solution stirring and dissolving, in 20 ~ 25 ℃, drip bromine liquid, finish, continue to stir 1 one hours, elutriation, filters, be washed to neutrality, be dried to obtain 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone;
(d) replacement(metathesis)reaction:
By 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone joined in Potassium ethanoate-dipolar aprotic solvent, in 35-40 ℃ of reaction 30 minutes, reclaim under reduced pressure dipolar aprotic solvent, filters, and is washed to neutrality, dry, obtain 11 α, 17 alpha-dihydroxy-s-21-acetic ester Progesterone;
(e) oxidizing reaction:
By 11 α, 17 alpha-dihydroxy-s-21-acetic ester Progesterone joins in glacial acetic acid, stirs, then adds the Manganous chloride tetrahydrate aqueous solution, 5-10 ℃ starts to drip chromium anhydride solution, adds rear insulation reaction more than 4 hours, elutriation, filter, be washed to neutrality, obtain cortisone acetate.
11 Alpha-hydroxy-16 α in described step (a), 17 α-epoxy Progesterone: bromine hydracid=1g:3 ~ 5ml, 11 α in described step (b), 17 alpha-dihydroxy--16 β-bromine Progesterone: ethanol: glacial acetic acid: Raney's nickel=1g:20 ~ 25ml:0.8 ~ 1.0ml:0.5 ~ 0.7g, 11 α in described step (c), 17 alpha-dihydroxy-s-Progesterone: chloroform: hydrochloric acid-alcohol mixeding liquid: the amount ratio of bromine liquid is 1g:7ml:0.2ml:3.6ml, described bromine liquid is the mixture of bromine and chloroform, bromine: the ratio of chloroform is 0.6ml:3ml, hydrochloric acid in described hydrochloric acid-alcohol mixeding liquid: ethanol is 4ml:1ml, 11 α in described step (d), 17 alpha-dihydroxy-s-21-bromine Progesterone: the amount ratio of Potassium ethanoate-dipolar aprotic solvent is 1g:15.97ml, in described step (d), dipolar aprotic solvent comprises dimethyl formamide or dimethyl sulfoxide (DMSO), in described step (d), the preparation method of Potassium ethanoate-dipolar aprotic solvent is: the salt of wormwood of proportional quantity is joined in dipolar aprotic solvent, be heated to 50 ℃, drip glacial acetic acid, finish and continue reaction 30 minutes, wherein salt of wormwood: dipolar aprotic solvent: the amount ratio of glacial acetic acid is: 1g:10.9ml:0.4ml, 11 α in described step (e), 17 alpha-dihydroxy-s-21-acetic ester Progesterone: in glacial acetic acid: the Manganous chloride tetrahydrate aqueous solution: the amount ratio of chromium anhydride solution is 1g:0.8ml:0.8ml:0.3ml, described manganese chloride solution concentration is 1g/ml, described chromium anhydride solution concentration is 1g/ml.
This preparation method's reaction formula is:
Embodiment 1:
A preparation method for cortisone acetate, comprises the steps:
(a) upper bromine reaction: preparation 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone
In reaction flask, drop into 11 Alpha-hydroxy-16 α, 17 α-epoxy Progesterone 50g, bromine hydracid 150ml, in 5 ~ 10 ℃ of stirring reactions 5 hours; React complete, add water 1000ml elutriation, filter, wash with water to neutrality, drain, dry, obtain 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone 60g, TLC maximum point 0.7%;
(b) debromination: preparation 11 α, 17 alpha-dihydroxy-Progesterone
In reaction flask, drop into 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone 50g, ethanol 1000ml are warming up to 40-45 ℃ of stirring and dissolving, then add successively 40ml glacial acetic acid, Raney's nickel 25g logical hydrogen, insulation reaction 3 hours, filter, concentrating under reduced pressure reclaims ethanol, filters elutriation to neutral, drain, dry, obtain 11 α, 17 alpha-dihydroxy-Progesterone 40g.MP(fusing point): 213 ~ 218 ℃, TLC(tlc) maximum point 0.5%;
(c) bromination reaction: preparation 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone
In reaction flask, drop into 11 α, 17 alpha-dihydroxy-s-Progesterone 40g, chloroform 280ml, add again hydrochloric acid-ethanol 8ml stirring and dissolving, in 20 ~ 25 ℃ of dropping 144ml bromine liquid, within 1 hour, dropwise, continue to stir one hour, add water 1000ml elutriation, filter, wash with water to neutrality, drain, dry, obtain 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone 47.6g;
(d) replacement(metathesis)reaction: preparation 11 α, 17 alpha-dihydroxy-s-21-acetic ester Progesterone
In reaction flask, drop into 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone 40g, Potassium ethanoate-dimethyl formamide 639ml, stirring and dissolving, be warming up to 35-40 ℃ of reaction 30 minutes, concentrating under reduced pressure, filters, and is washed to neutrality, dry, obtain 11 α, 17 alpha-dihydroxy-s-21-acetic ester Progesterone 37.2g.MP:220 ~ 225 ℃, TLC maximum point 0.6%;
(e) oxidizing reaction: prepare cortisone acetate
In reaction flask, drop into 11 α, 17 alpha-dihydroxy-21-acetic ester Progesterone 30g, glacial acetic acid 24ml, stirs, add again Manganous chloride tetrahydrate aqueous solution 24ml, 5-10 ℃ starts to drip chromium anhydride solution 9ml, adds rear insulation reaction more than 4 hours, elutriation, filter, elutriation is to neutral, dry, obtains cortisone acetate 29.1g.MP:227 ~ 232 ℃, HPLC(high performance liquid chromatography) purity: 98.2%, yield is 103%.
Embodiment 2:
A preparation method for cortisone acetate, comprises the steps:
(a) upper bromine reaction: preparation 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone
In reaction flask, drop into 11 Alpha-hydroxy-16 α, 17 α-epoxy Progesterone 50g, bromine hydracid 150ml, in 5 ~ 10 ℃ of stirring reactions 5 hours; React complete, add water 1000ml elutriation, filter, wash with water to neutrality, drain, dry, obtain 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone 60g, TLC maximum point 0.7%;
(b) debromination: preparation 11 α, 17 alpha-dihydroxy-Progesterone
In reaction flask, drop into 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone 50g, ethanol 1000ml are warming up to 40-45 ℃ of stirring and dissolving, then add successively 40ml glacial acetic acid, Raney's nickel 25g logical hydrogen, insulation reaction 3 hours, filter, concentrating under reduced pressure reclaims ethanol, filters elutriation to neutral, drain, dry, obtain 11 α, 17 alpha-dihydroxy-Progesterone 40g.MP(fusing point): 213 ~ 218 ℃, TLC(tlc) maximum point 0.5%;
(c) bromination reaction: preparation 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone
In reaction flask, drop into 11 α, 17 alpha-dihydroxy-s-Progesterone 40g, chloroform 280ml, add again hydrochloric acid-ethanol 8ml stirring and dissolving, in 20 ~ 25 ℃ of dropping 144ml bromine liquid, within 1 hour, dropwise, continue to stir one hour, add water 1000ml elutriation, filter, wash with water to neutrality, drain, dry, obtain 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone 47.6g;
(d) replacement(metathesis)reaction: preparation 11 α, 17 α, 21 trihydroxy-Progesterone
In reaction flask, drop into 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone 40g, Potassium ethanoate-dimethyl sulfoxide (DMSO) 639ml, stirring and dissolving, be warming up to 35-40 ℃ of reaction 30 minutes, concentrating under reduced pressure, filters, and is washed to neutrality, dry, obtain 11 α, 17 α, 21-trihydroxy-Progesterone 37g.MP:219 ~ 223 ℃, TLC maximum point 0.7%;
(e) oxidizing reaction: prepare cortisone acetate
In reaction flask, drop into 11 α, 17 alpha-dihydroxy-21-acetic ester Progesterone 30g, glacial acetic acid 24ml, stirs, add again Manganous chloride tetrahydrate aqueous solution 24ml, 5-10 ℃ starts to drip chromium anhydride solution 9ml, adds rear insulation reaction more than 4 hours, elutriation, filter, elutriation is to neutral, dry, obtains cortisone acetate 29g.After testing, cortisone acetate MP:228 ~ 233 prepared by the present embodiment, HPLC purity: 98.0%, yield is 102.5%.
Although contriver has done comparatively detailed elaboration and has enumerated technical scheme of the present invention, be to be understood that, for one of this area those skilled in the art, above-described embodiment is made modification, accommodation or adopted the replacement scheme being equal to is obvious, all can not depart from the essence of spirit of the present invention, the term occurring in the present invention, for the elaboration to invention technical scheme and understanding, can not be construed as limiting the invention.
Claims (8)
1. a preparation method for cortisone acetate, with 11 Alpha-hydroxy-16 α, 17 α-epoxy Progesterone is raw material, comprises the following steps:
(a) upper bromine reaction:
By 11 Alpha-hydroxy-16 α, 17 α-epoxy Progesterone adds in bromine hydracid, in 5 ~ 10 ℃ of stirring reactions, more than 5 hours, reacts complete, adds water elutriation, filters, and washes with water to neutrality, dry, obtains 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone;
(b) debromination:
By 11 α, 17 alpha-dihydroxy--16 β-bromine Progesterone add and in ethanol, are warming up to 40-45 ℃ of stirring and dissolving, then add successively glacial acetic acid, active Raney's nickel logical hydrogen, insulation reaction 3 hours, filters, and concentrating under reduced pressure reclaims solvent, filtered water is washed till neutrality, dry, obtain 11 α, 17 alpha-dihydroxy-Progesterone;
(c) bromination reaction:
By 11 α, 17 alpha-dihydroxy-Progesterone add in chloroform, then add hydrochloric acid-alcohol mixed solution stirring and dissolving, in 20 ~ 25 ℃, drip bromine liquid, finish, continue to stir 1 one hours, elutriation, filters, be washed to neutrality, be dried to obtain 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone;
(d) replacement(metathesis)reaction:
By 11 α, 17 alpha-dihydroxy-s-21-bromine Progesterone joined in Potassium ethanoate-dipolar aprotic solvent, in 35-40 ℃ of reaction 30 minutes, reclaim under reduced pressure dipolar aprotic solvent, filters, and is washed to neutrality, dry, obtain 11 α, 17 alpha-dihydroxy-s-21-acetic ester Progesterone;
(e) oxidizing reaction:
By 11 α, 17 alpha-dihydroxy-s-21-acetic ester Progesterone joins in glacial acetic acid, stirs, then adds the Manganous chloride tetrahydrate aqueous solution, 5-10 ℃ starts to drip chromium anhydride solution, adds rear insulation reaction more than 4 hours, elutriation, filter, be washed to neutrality, obtain cortisone acetate.
2. the preparation method of a kind of cortisone acetate according to claim 1, is characterized in that: 11 Alpha-hydroxy-16 α in described step (a), 17 α-epoxy Progesterone: bromine hydracid=1g:3 ~ 5ml.
3. the preparation method of a kind of cortisone acetate according to claim 1, it is characterized in that: 11 α in described step (b), 17 alpha-dihydroxy--16 β-bromine Progesterone: ethanol: glacial acetic acid: Raney's nickel=1g:20 ~ 25ml:0.8 ~ 1.0ml:0.5 ~ 0.7g.
4. the preparation method of a kind of cortisone acetate according to claim 1, it is characterized in that: 11 α in described step (c), 17 alpha-dihydroxy-s-Progesterone: chloroform: hydrochloric acid-alcohol mixeding liquid: the amount ratio of bromine liquid is 1g:7ml:0.2ml:3.6ml, described bromine liquid is the mixture of bromine and chloroform, bromine: the ratio of chloroform is 0.6ml:3ml, hydrochloric acid in described hydrochloric acid-alcohol mixeding liquid: ethanol is 4ml:1ml.
5. the preparation method of a kind of cortisone acetate according to claim 1, is characterized in that: 11 α in described step (d), 17 alpha-dihydroxy-s-21-bromine Progesterone: the amount ratio of Potassium ethanoate-dipolar aprotic solvent is 1g:15.97ml.
6. the preparation method of a kind of cortisone acetate according to claim 1, is characterized in that: in described step (d), dipolar aprotic solvent is dimethyl formamide or dimethyl sulfoxide (DMSO).
7. the preparation method of a kind of cortisone acetate according to claim 1, it is characterized in that: in described step (d), the preparation method of Potassium ethanoate-dipolar aprotic solvent is: the salt of wormwood of proportional quantity is joined in dipolar aprotic solvent, be heated to 50 ℃, drip glacial acetic acid, finish and continue reaction 30 minutes, wherein salt of wormwood: dipolar aprotic solvent: the amount ratio of glacial acetic acid is: 1g:10.9ml:0.4ml.
8. the preparation method of a kind of cortisone acetate according to claim 1, it is characterized in that: 11 α in described step (e), 17 alpha-dihydroxy-s-21-acetic ester Progesterone: in glacial acetic acid: the Manganous chloride tetrahydrate aqueous solution: the amount ratio of chromium anhydride solution is 1g:0.8ml:0.8ml:0.3ml, described manganese chloride solution concentration is 1g/ml, and described chromium anhydride solution concentration is 1g/ml.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111777654A (en) * | 2020-06-11 | 2020-10-16 | 浙江神洲药业有限公司 | Preparation method of prednisone |
| CN112279767A (en) * | 2020-10-29 | 2021-01-29 | 陕西嘉禾生物科技股份有限公司 | Preparation method of diacerein |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111777654A (en) * | 2020-06-11 | 2020-10-16 | 浙江神洲药业有限公司 | Preparation method of prednisone |
| CN111777654B (en) * | 2020-06-11 | 2021-08-10 | 浙江神洲药业有限公司 | Preparation method of prednisone |
| CN112279767A (en) * | 2020-10-29 | 2021-01-29 | 陕西嘉禾生物科技股份有限公司 | Preparation method of diacerein |
| CN112279767B (en) * | 2020-10-29 | 2023-02-03 | 陕西嘉禾生物科技股份有限公司 | Preparation method of diacerein |
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